Reversal of antifungal resistance mediated by ABC efflux pumps from Candida albicans functionally expressed in yeast

The enhanced efflux of antifungal drugs through ATP-binding cassette (ABC) transporters constitutes a major cause of clinical multidrug resistance (MDR). The inhibition of drug efflux pumps by specific compounds is considered to be a feasible strategy to overcome clinical antifungal resistance. Therefore, several blockers of mammalian and yeast ABC drug pumps, including FK506, propafenones, as well as the antifungal drug terbinafine were tested for their capacity to reverse CDR-mediated azole resistance in bakers yeast and in clinical isolates of Candida albicans. We have functionally expressed the C. albicans Cdr1p and Cdr2p transporters in hypersensitive Saccharomyces cerevisiae recipient strains lacking several endogenous ABC pumps. Cdr1p and Cdr2p were functional in yeast, as they conferred pronounced drug resistance to known antifungal drugs, including azoles and terbinafine. We employ two functional assays to demonstrate that ABC pump inhibitors reverse CDR-mediated antifungal resistance, thereby restoring drug susceptibility of yeast cells and resistant clinical isolates. Our results suggest that reversal of antifungal resistance can be achieved through ABC pump-dependent and independent mechanisms.